The adult patients lost a substantial amount of weight -- 51 kg (112 lbs) after 42 weeks for one patient and 20.5 kg (45 lbs) after 12 weeks for the other -- and had reduced hunger, according to the pilot phase II open-label study, according to Peter Kühnen, MD, at the Charité-Universitats-medizin Berlin in Germany, and colleagues.

The agent binds and activates melanocortin-4 receptor (MC4R), along with MC3R and MC1R selectively over MC5R and MC2R, so that food intake is reduced.

"The results of the current study are exciting for these rare patients, their families, and treating clinicians," wrote Marc Reitman, MD, PhD, of the NIH's National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., in an accompanying editorial. "Yet interpretation requires caution, because the study includes only two patients (representing two-thirds of the world's known adult population with proopiomelanocortin deficiency)."

Other research has shown that setmelanotide possibly increases resting energy expenditure as well, Reitman noted.

Patients with POMC deficiency also have secondary hypocortisolism and, during the neo-natal period, are at risk of hypoglycemia, hyperbilirubinemia, and cholestasis. But those symptoms can be reversed with hydrocortisone, Kühnen's group wrote. Adults with the condition are extremely rare, perhaps because of the high mortality in early adulthood.

One patient was a 21-year-old from Germany with a body mass index of 50 kg/m2. She had not undergone menarche and had other metabolic disturbances. The other patient, a 26-year-old woman from France, had severe obesity (54 kg/m2 at the time of the presentation) since a young child and had been receiving hydrocortisone-replacement therapy almost since birth.

Both patients had hyperphagia and severe insulin resistance. They reported being extremely dissatisfied with their quality of life.

Setmelanotide (RM-493) was administered once daily by subcutaneous injection, starting at a dose of 0.25 mg in the German patient and 0.5 mg in the French patient. Dose escalation occurred in weekly increments, to 0.5 mg per day in the first patient and then, in both patients, to 1.0 mg and finally to 1.5 mg.

While the patients' blood pressure didn't increase with dose escalation. Reitman added that concern over increases in blood pressure had slowed the development of melanocortin-agonist drugs.

"The absence of a blood-pressure increase with setmelanotide is welcome and intriguing," he wrote. "Understanding the differences between the signaling mechanisms and pharmacokinetics of setmelanotide and those of endogenous MSH might guide improved treatment of patients with pro-opiomelanocortin deficiency."

The patient on the drug for 42 weeks was initially taken off of the drug at 13 weeks because of regulatory obligations, the authors wrote. But her hunger increased, and she "had an episode of anger and dejection." She was restarted on the drug after 3 weeks, and she lost a third of her body weight by 42 weeks. The drug did not appear to affect pubertal development in the patients, the authors stated.

No serious adverse events were linked to the drug, but both patients reported infrequent dry mouth, and mild pain at the injection site the first time the injection was given. The skin and hair color of both patients darkened over the duration of the study.

It isn't known how the drug would affect patients with common forms of obesity. That question, according to Reitman, is the elephant in the room. He pointed to the disappointing results of leptin replacement therapy on patients with common obesity. But "MC4R is an unusual receptor in that heterozygous loss of function causes a phenotype, whereas for many receptors, loss of one allele produces no obvious effect," he wrote.

That could mean that the MC4R agonist is a "sweet spot" for drug therapy, but the answer to that is years off -- and many more patients away, Reitman wrote. The authors wrote that other patients with rare genetic defects might benefit from the study, like those with Prader-Willi syndrome or epigenetic variations in POMC.

Reitman added that future studies need to have a placebo-controlled crossover design to "bolster these open-label results" and to figure out how setmelanotide affects insulin secretion and blood pressure without the confounding variables of food intake and weight loss.

Setmelanotide was supplied by Rhythm Pharmaceuticals. A co-author is a company employee.

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